SARS-CoV-2 501Y.V2 escapes neutralization by South African COVID-19 donor plasma

Nature Medicine, Journal Year: 2021, Volume and Issue: 27(4), P. 622 - 625

Published: March 2, 2021

Language: Английский

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Circular RNA vaccines against SARS-CoV-2 and emerging variants

Cell, Journal Year: 2022, Volume and Issue: 185(10), P. 1728 - 1744.e16

Published: April 1, 2022

As the emerging variants of SARS-CoV-2 continue to drive worldwide pandemic, there is a constant demand for vaccines that offer more effective and broad-spectrum protection. Here, we report circular RNA (circRNA) vaccine elicited potent neutralizing antibodies T cell responses by expressing trimeric RBD spike protein, providing robust protection against in both mice rhesus macaques. Notably, circRNA enabled higher durable antigen production than 1mΨ-modified mRNA proportion distinct Th1-skewed immune responses. Importantly, found circRNARBD-Omicron induced Omicron but not Delta variant. In contrast, circRNARBD-Delta protected or functioned as booster after two doses either native- Delta-specific vaccination, making it favorable choice current concern (VOCs) SARS-CoV-2.

Language: Английский

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Molecular mechanism of interaction between SARS-CoV-2 and host cells and interventional therapy

Signal Transduction and Targeted Therapy, Journal Year: 2021, Volume and Issue: 6(1)

Published: June 11, 2021

Abstract The pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome 2 (SARS-CoV-2) infection has resulted in an unprecedented setback for global economy and health. SARS-CoV-2 exceptionally high level transmissibility extremely broad tissue tropism. However, the underlying molecular mechanism responsible sustaining this degree virulence remains largely unexplored. In article, we review current knowledge crucial information about how attaches on surface host cells through a variety receptors, such as ACE2, neuropilin-1, AXL, antibody–FcγR complexes. We further explain its spike (S) protein undergoes conformational transition from prefusion to postfusion with help proteases like furin, TMPRSS2, cathepsins. then ongoing experimental studies clinical trials antibodies, peptides, or small-molecule compounds anti-SARS-CoV-2 activity, discuss these antiviral therapies targeting host–pathogen interaction could potentially suppress viral attachment, reduce exposure fusion peptide curtail membrane block formation six-helix bundle (6-HB) core. Finally, specter rapidly emerging variants deserves serious broad-spectrum drugs vaccines long-term prevention control COVID-19 future.

Language: Английский

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SARS-CoV-2 501Y.V2 escapes neutralization by South African COVID-19 donor plasma

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2021, Volume and Issue: unknown

Published: Jan. 19, 2021

Abstract SARS-CoV-2 501Y.V2 (B.1.351), a novel lineage of coronavirus causing COVID-19, contains substitutions in two immunodominant domains the spike protein. Here, we show that pseudovirus expressing protein completely escapes three classes therapeutically relevant antibodies. This also exhibits substantial to complete escape from neutralization, but not binding, by convalescent plasma. These data highlight prospect reinfection with antigenically distinct variants and foreshadows reduced efficacy spike-based vaccines.

Language: Английский

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Nanobodies from camelid mice and llamas neutralize SARS-CoV-2 variants

Nature, Journal Year: 2021, Volume and Issue: 595(7866), P. 278 - 282

Published: June 7, 2021

Abstract Since the start of COVID-19 pandemic, SARS-CoV-2 has caused millions deaths worldwide. Although a number vaccines have been deployed, continual evolution receptor-binding domain (RBD) virus challenged their efficacy. In particular, emerging variants B.1.1.7, B.1.351 and P.1 (first detected in UK, South Africa Brazil, respectively) compromised efficacy sera from patients who recovered immunotherapies that received emergency use authorization 1–3 . One potential alternative to avert viral escape is camelid VHHs (variable heavy chain domains antibody (also known as nanobodies)), which can recognize epitopes are often inaccessible conventional antibodies 4 Here, we isolate anti-RBD nanobodies llamas mice engineered produce cloned alpacas, dromedaries Bactrian camels. We identified two groups highly neutralizing nanobodies. Group 1 circumvents antigenic drift by recognizing an RBD region conserved coronaviruses but rarely targeted human antibodies. 2 almost exclusively focused RBD–ACE2 interface does not neutralize carry E484K or N501Y substitutions. However, group retain full neutralization activity against these when expressed homotrimers, and—to our knowledge—rival most potent produced date. These findings suggest multivalent overcome mutations through separate mechanisms: enhanced avidity for ACE2-binding recognition largely Therefore, although new mutants will continue emerge, represent promising tools prevent mortality compromised.

Language: Английский

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A highly photostable and bright green fluorescent protein

Nature Biotechnology, Journal Year: 2022, Volume and Issue: 40(7), P. 1132 - 1142

Published: April 25, 2022

The low photostability of fluorescent proteins is a limiting factor in many applications fluorescence microscopy. Here we present StayGold, green protein (GFP) derived from the jellyfish Cytaeis uchidae. StayGold over one order magnitude more photostable than any currently available and has cellular brightness similar to mNeonGreen. We used image dynamics endoplasmic reticulum (ER) with high spatiotemporal resolution several minutes using structured illumination microscopy (SIM) observed substantially less photobleaching GFP variant optimized for stability ER. Using fusions SIM, also imaged mitochondrial fusion fission mapped viral spike fixed cells infected severe acute respiratory syndrome coronavirus 2. As dimer, created tandem dimer version that allowed us observe microtubules excitatory post-synaptic density neurons. will reduce limitations imposed by photobleaching, especially live cell or volumetric imaging.

Language: Английский

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Comprehensive structure and functional adaptations of the yeast nuclear pore complex

Cell, Journal Year: 2022, Volume and Issue: 185(2), P. 361 - 378.e25

Published: Jan. 1, 2022

Nuclear pore complexes (NPCs) mediate the nucleocytoplasmic transport of macromolecules. Here we provide a structure isolated yeast NPC in which inner ring is resolved by cryo-EM at sub-nanometer resolution to show how flexible connectors tie together different structural and functional layers. These may be targets for phosphorylation regulated disassembly cells with an open mitosis. Moreover, some nucleoporin pairs factors have similar interaction motifs, suggests evolutionary mechanistic link between assembly transport. We evidence three major variants that foreshadow specializations nuclear periphery. Cryo-electron tomography extended these studies, providing model situ radially expanded ring. Our comprehensive reveals features basket central transporter, role lumenal Pom152 restricting dilation, highlights plasticity required

Language: Английский

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Nanobody cocktails potently neutralize SARS-CoV-2 D614G N501Y variant and protect mice

Proceedings of the National Academy of Sciences, Journal Year: 2021, Volume and Issue: 118(19)

Published: April 23, 2021

Significance Neutralizing antibodies are important for immunity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and as therapeutics the prevention treatment of COVID-19. We identified high-affinity nanobodies SARS-CoV-2 receptor-binding domain found that nanobody cocktails consisting two noncompeting were able to block ACE2 engagement with RBD variants present in human populations potently neutralize both wild-type N501Y D614G variant at low concentrations. Prophylactic administration reduced viral loads mice infected virus, showing useful prophylactic agents SARS-CoV-2.

Language: Английский

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Inhalable Nanobody (PiN-21) prevents and treats SARS-CoV-2 infections in Syrian hamsters at ultra-low doses

Science Advances, Journal Year: 2021, Volume and Issue: 7(22)

Published: May 26, 2021

Globally, there is an urgency to develop effective, low-cost therapeutic interventions for coronavirus disease 2019 (COVID-19). We previously generated the stable and ultrapotent homotrimeric Pittsburgh inhalable Nanobody 21 (PiN-21). Using Syrian hamsters that model moderate severe COVID-19 disease, we demonstrate high efficacy of PiN-21 prevent treat SARS-CoV-2 infection. Intranasal delivery at 0.6 mg/kg protects infected animals from weight loss substantially reduces viral burdens in both lower upper airways compared control. Aerosol facilitates deposition throughout respiratory tract dose minimization 0.2 mg/kg. Inhalation treatment quickly reverses animals' after infection, decreases lung titers by 6 logs leading drastically mitigated pathology, prevents pneumonia. Combined with marked stability low production cost, this innovative therapy may provide a convenient cost-effective option mitigate ongoing pandemic.

Language: Английский

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A potent SARS-CoV-2 neutralising nanobody shows therapeutic efficacy in the Syrian golden hamster model of COVID-19

Nature Communications, Journal Year: 2021, Volume and Issue: 12(1)

Published: Sept. 22, 2021

SARS-CoV-2 remains a global threat to human health particularly as escape mutants emerge. There is an unmet need for effective treatments against COVID-19 which neutralizing single domain antibodies (nanobodies) have significant potential. Their small size and stability mean that nanobodies are compatible with respiratory administration. We report four (C5, H3, C1, F2) engineered homotrimers pmolar affinity the receptor binding (RBD) of spike protein. Crystal structures show C5 H3 overlap ACE2 epitope, whilst C1 F2 bind different epitope. Cryo Electron Microscopy shows results in all down arrangement Spike neutralize Victoria strain, highly transmissible Alpha (B.1.1.7 first identified Kent, UK) strain also neutralizes Beta (B.1.35, South Africa). Administration C5-trimer via route showed potent therapeutic efficacy Syrian hamster model separately, prophylaxis. The molecule was similarly by intraperitoneal injection.

Language: Английский

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